This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Title: NMR-based discovery of apoptotic agents as anti-cancer leadsIn the last decade, certain biological molecules in cells have beenidentified to be accountable for the development of cancer, if they bindto other biological molecules. One family of these biological moleculesrepresents the proteins of the Bcl-2 family. These proteins directlyrelate to many cancers such as B-cells lymphomas, prostate cancers,colorectal adenocarcinomas, breast cancers and lung cancers.It has been shown that these unfavorable binding interactions betweenthe proteins of the Bcl-2 family can be disrupted by drug molecules.Disrupting these unfavorable interactions leads in higher organisms to acellular process termed apoptosis or programmed cell death. Hence,discovery and/or development of potent drug molecules that induce celldeath represent a potential new cure for many cancers. The main goal ofthis proposal is to develop novel anticancer drugs that induce apoptosisof cancer cells. We will study our lead compounds in complex with thetarget protein Bcl-XL by NMR to guide the optimization and design ofmore potent compounds. NMR will also be a key analytical method todetermine whether our lead compounds are binding at the actual bindingsite of the target protein Bcl-XL. Our proposed approach to find drugmolecules has enormous potential not only for the discovery of newanticancer drugs but it also has potential to influence biological andmedical sciences in general.